JPS635027B2 - - Google Patents
Info
- Publication number
- JPS635027B2 JPS635027B2 JP57030921A JP3092182A JPS635027B2 JP S635027 B2 JPS635027 B2 JP S635027B2 JP 57030921 A JP57030921 A JP 57030921A JP 3092182 A JP3092182 A JP 3092182A JP S635027 B2 JPS635027 B2 JP S635027B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- furylcarbonyl
- nax
- ethyl
- yield
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 9
- 239000003524 antilipemic agent Substances 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- -1 furyl oxazolyl acetic acid derivative Chemical class 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- RKEARERKYHKVQD-UHFFFAOYSA-N 2-amino-1-(furan-2-yl)ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC=CO1 RKEARERKYHKVQD-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- CHOQKBKQDVRWOT-UHFFFAOYSA-N 2-amino-1-(furan-3-yl)ethanone;hydrochloride Chemical compound Cl.NCC(=O)C=1C=COC=1 CHOQKBKQDVRWOT-UHFFFAOYSA-N 0.000 description 4
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000012024 dehydrating agents Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- OUUDCURGIXYQCL-UHFFFAOYSA-N 2-amino-1-(furan-3-yl)ethanone Chemical compound NCC(=O)C=1C=COC=1 OUUDCURGIXYQCL-UHFFFAOYSA-N 0.000 description 2
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical compound FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- GEAUWUZGLTXKCJ-UHFFFAOYSA-N n-[2-(furan-2-yl)-2-oxoethyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC(=O)C1=CC=CO1 GEAUWUZGLTXKCJ-UHFFFAOYSA-N 0.000 description 2
- ZUMGFYQZTDTOIZ-UHFFFAOYSA-N n-[2-(furan-2-yl)-2-oxoethyl]acetamide Chemical compound CC(=O)NCC(=O)C1=CC=CO1 ZUMGFYQZTDTOIZ-UHFFFAOYSA-N 0.000 description 2
- XCLFNSGGTRHDBR-UHFFFAOYSA-N n-[2-(furan-2-yl)-2-oxoethyl]cyclohexanecarboxamide Chemical compound C=1C=COC=1C(=O)CNC(=O)C1CCCCC1 XCLFNSGGTRHDBR-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- CQHYICHMGNSGQH-UHFFFAOYSA-N 1,3-oxazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CO1 CQHYICHMGNSGQH-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 1
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- KOJIULHCZVCANA-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-5-(furan-2-yl)-1,3-oxazol-4-yl]acetic acid Chemical compound OC(=O)CC=1N=C(C=2C=CC(Cl)=CC=2)OC=1C1=CC=CO1 KOJIULHCZVCANA-UHFFFAOYSA-N 0.000 description 1
- DGQYYEJWTUWJBR-UHFFFAOYSA-N 2-amino-1-(furan-2-yl)ethanone Chemical compound NCC(=O)C1=CC=CO1 DGQYYEJWTUWJBR-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 description 1
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 description 1
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- HFMJQEZNSGZLMO-UHFFFAOYSA-N 4-chloro-n-[2-(furan-2-yl)-2-oxoethyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC(=O)C1=CC=CO1 HFMJQEZNSGZLMO-UHFFFAOYSA-N 0.000 description 1
- LEPLGTJRKGCSTN-UHFFFAOYSA-N 4-chloro-n-[2-(furan-3-yl)-2-oxoethyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCC(=O)C1=COC=C1 LEPLGTJRKGCSTN-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- CKXVLNAVTFVHEB-UHFFFAOYSA-N 4-fluoro-n-[2-(furan-2-yl)-2-oxoethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NCC(=O)C1=CC=CO1 CKXVLNAVTFVHEB-UHFFFAOYSA-N 0.000 description 1
- ZCOJGBYZZVUHFY-UHFFFAOYSA-N 4-fluoro-n-[2-(furan-3-yl)-2-oxoethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NCC(=O)C1=COC=C1 ZCOJGBYZZVUHFY-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ABYBUOHSJCFYNC-UHFFFAOYSA-N 5-(furan-3-yl)-1,3-oxazole Chemical compound O1C=CC(C=2OC=NC=2)=C1 ABYBUOHSJCFYNC-UHFFFAOYSA-N 0.000 description 1
- DXKAWTDZKYJZRD-UHFFFAOYSA-N 5-(furan-3-yl)-1,3-oxazole-4-carboxylic acid Chemical compound N1=COC(C2=COC=C2)=C1C(=O)O DXKAWTDZKYJZRD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- URSTXNUDNQWACG-UHFFFAOYSA-N ethyl 2-[5-(furan-2-yl)-2-(4-methoxyphenyl)-1,3-oxazol-4-yl]acetate Chemical compound CCOC(=O)CC=1N=C(C=2C=CC(OC)=CC=2)OC=1C1=CC=CO1 URSTXNUDNQWACG-UHFFFAOYSA-N 0.000 description 1
- ZJDZCTGBEACIKB-UHFFFAOYSA-N ethyl 3-(cyclohexanecarbonylamino)-4-(furan-2-yl)-4-oxobutanoate Chemical compound C=1C=COC=1C(=O)C(CC(=O)OCC)NC(=O)C1CCCCC1 ZJDZCTGBEACIKB-UHFFFAOYSA-N 0.000 description 1
- LKUNVNYDFPGKMY-UHFFFAOYSA-N ethyl 3-[(3,4-dichlorobenzoyl)amino]-4-(furan-3-yl)-4-oxobutanoate Chemical compound C1=COC=C1C(=O)C(CC(=O)OCC)NC(=O)C1=CC=C(Cl)C(Cl)=C1 LKUNVNYDFPGKMY-UHFFFAOYSA-N 0.000 description 1
- GTCHZBUMKQKKEF-UHFFFAOYSA-N ethyl 3-[(4-fluorobenzoyl)amino]-4-(furan-2-yl)-4-oxobutanoate Chemical compound C=1C=COC=1C(=O)C(CC(=O)OCC)NC(=O)C1=CC=C(F)C=C1 GTCHZBUMKQKKEF-UHFFFAOYSA-N 0.000 description 1
- YKQQIEOUEZZSQC-UHFFFAOYSA-N ethyl 3-acetamido-4-(furan-2-yl)-4-oxobutanoate Chemical compound CCOC(=O)CC(NC(C)=O)C(=O)C1=CC=CO1 YKQQIEOUEZZSQC-UHFFFAOYSA-N 0.000 description 1
- LJVTUDCNOJEWTJ-UHFFFAOYSA-N ethyl 3-benzamido-4-(furan-3-yl)-4-oxobutanoate Chemical compound C1=COC=C1C(=O)C(CC(=O)OCC)NC(=O)C1=CC=CC=C1 LJVTUDCNOJEWTJ-UHFFFAOYSA-N 0.000 description 1
- DOWJUSPHGWWKMY-UHFFFAOYSA-N ethyl 4-(furan-2-yl)-3-(2-methylpropanoylamino)-4-oxobutanoate Chemical compound CCOC(=O)CC(NC(=O)C(C)C)C(=O)C1=CC=CO1 DOWJUSPHGWWKMY-UHFFFAOYSA-N 0.000 description 1
- RNXRDHLRBXUKGL-UHFFFAOYSA-N ethyl 4-(furan-2-yl)-4-oxo-3-(pentanoylamino)butanoate Chemical compound CCCCC(=O)NC(CC(=O)OCC)C(=O)C1=CC=CO1 RNXRDHLRBXUKGL-UHFFFAOYSA-N 0.000 description 1
- DTLDXAUFLRHRQQ-UHFFFAOYSA-N ethyl 4-(furan-2-yl)-4-oxobutanoate Chemical compound CCOC(=O)CCC(=O)C1=CC=CO1 DTLDXAUFLRHRQQ-UHFFFAOYSA-N 0.000 description 1
- QOKDLBATRLNRGK-UHFFFAOYSA-N ethyl 4-(furan-3-yl)-4-oxobutanoate Chemical compound CCOC(=O)CCC(=O)C=1C=COC=1 QOKDLBATRLNRGK-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FPSRMGOCTYJYRL-UHFFFAOYSA-N heptyl 2-[2-(4-chlorophenyl)-5-(furan-2-yl)-1,3-oxazol-4-yl]acetate Chemical compound CCCCCCCOC(=O)CC=1N=C(C=2C=CC(Cl)=CC=2)OC=1C1=CC=CO1 FPSRMGOCTYJYRL-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- QTBFPMKWQKYFLR-UHFFFAOYSA-N isobutyl chloride Chemical compound CC(C)CCl QTBFPMKWQKYFLR-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JZSAEGOONAZWSA-UHFFFAOYSA-N methyl 1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC=N1 JZSAEGOONAZWSA-UHFFFAOYSA-N 0.000 description 1
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- PBIULHQYEUKHPR-UHFFFAOYSA-N methyl 5-(furan-3-yl)-1,3-oxazole-4-carboxylate Chemical compound N1=COC(C2=COC=C2)=C1C(=O)OC PBIULHQYEUKHPR-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- UENJRTOGKKSMSB-UHFFFAOYSA-N n-[2-(furan-2-yl)-2-oxoethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NCC(=O)C1=CC=CO1 UENJRTOGKKSMSB-UHFFFAOYSA-N 0.000 description 1
- FHCIKSCEFONQSB-UHFFFAOYSA-N n-[2-(furan-2-yl)-2-oxoethyl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NCC(=O)C1=CC=CO1 FHCIKSCEFONQSB-UHFFFAOYSA-N 0.000 description 1
- NLFMGFZCSIOZPU-UHFFFAOYSA-N n-[2-(furan-3-yl)-2-oxoethyl]benzamide Chemical compound C1=COC=C1C(=O)CNC(=O)C1=CC=CC=C1 NLFMGFZCSIOZPU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- IPFNMMHEQQOVCN-UHFFFAOYSA-M potassium;2-[2-(4-chlorophenyl)-5-(furan-2-yl)-1,3-oxazol-4-yl]acetate Chemical compound [K+].[O-]C(=O)CC=1N=C(C=2C=CC(Cl)=CC=2)OC=1C1=CC=CO1 IPFNMMHEQQOVCN-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
Description
本発明は新規フリルオキサゾリル酢酸誘導体及
びその製法に関し、更に詳しくは一般式
（但し、R1はアルキル基、シクロアルキル基
もしくはフエニル基であるか、またはアルキル
基、アルコキシ基およびハロゲン原子から選ばれ
る１〜２個の置換基を有するフエニル基を表わ
し、R2は水素原子またはアルキル基を表わす）
で示されるフリルオキサゾリル酢酸誘導体もしく
はその薬理的に許容し得る塩及びその製法に関す
る。
本発明の化合物〔〕は優れた血清コレステロ
ール低下作用及び血清トリグリセリド低下作用を
有し、抗脂血剤として有用な医薬化合物である。
しかも、本発明化合物〔〕は肝機能障害の副作
用が少なく、また抗脂血剤にとつて好ましい随伴
作用である血小板凝集抑制作用を兼ねそなえてい
るという特徴を有している。
本発明の化合物の例としては、一般式〔〕に
おいて、R1がメチル基、エチル基、プロピル基、
イゾプロピル基、ブチル基、イソブチル基、ペン
チル基、イソペンチル基、ヘキシル基、の如き炭
素数１〜６個のアルキル基、シクロペンチル基、
シクロヘキシル基等の炭素数５〜６個のシクロア
ルキル基もしくはフエニル基であるか、またはベ
ンゼン環上にメチル基、エチル基の如き炭素数１
〜２個のアルキル基、メトキシ基、エトキシ基な
どの炭素数１〜２個のアルコキシ基および塩素、
フツ素、臭素、ヨウ素の如きハロゲン原子から選
ばれる１〜２個の置換基を有するフエニル基であ
り、R2が水素原子、またはメチル基、エチル基、
プロピル基、イソプロピル基、ブチル基、イソブ
チル基、ペンチル基、ヘキシル基、ヘプチル基、
オクチル基、ラウリル基の如き炭素数１〜12個の
アルキル基である化合物があげられる。これらの
うち好ましい化合物としては、一般式〔〕にお
いてR1がメチル基、エチル基、プロピル基、イ
ソプロピル基、ｎ・ブチル基、シクロヘキシル
基、フエニル基、４―クロロフエニル基、４―フ
ルオロフエニル基、４―メチルフエニル基、４―
メトキシフエニル基、３，４―ジクロロフエニル
基等であり、R2が水素原子またはエチル基であ
る化合物があげられる。また、とりわけ好ましい
化合物としてはR1がｎ・ブチル基、４―クロロ
フエニル基，４―フルオロフエニル基等であり、
R2が水素原子またはエチル基である化合物があ
げられる。
本発明によれば化合物〔〕は
(a) 一般式
（但し、R3はアルキル基を表わし、R1は前
記と同一意味を有する）
で示される３―アシルアミノプロピオン酸誘導
体を脱水閉環反応に付して一般式
（但し、R1及びR3は前記同一意味を有する）
で示されるフリルオキサゾリル酢酸エステル誘
導体とするか
(b) 上記(a)法で得られた化合物〔―ａ〕を加水
分解して一般式
（但し、R1は前記同一意味を有する）
で示されるフリルオキサゾリル酢酸誘導体とす
るか、或いは
(c) 上記(b)法で得られた化合物〔―ｂ〕をエス
テル化して一般式
（但し、R4はアルキル基を表わし、R1は前
記と同一意味を有する）
で示されるフリルオキサゾリル酢酸エステル誘導
体とすることにより製することができる。
以下、本発明の反応を詳細に説明する。
(a) 法
化合物〔〕の脱水閉環反応は適当な溶媒中脱
水剤を作用させることにより実施することができ
る。脱水剤としては例えばオキシ塩化リン、三塩
化リン、五塩化リン、チオニルクロリド、オキザ
リルクロリド、ホスゲン、五酸化リン等を用いる
ことができる。また、触媒的な脱水剤としては、
Ｐ・トルエンスルホン酸、硫酸なども好適に用い
ることができる。溶媒としては例えばクロロホル
ム、塩化メチレン、四塩化炭素、ベンゼン、トル
エン、キシレン、テトラヒドロフラン、ジメチル
ホルムアミド等が用いられる。本反応は−５℃〜
130℃で、とりわけ反応溶媒としてハロゲン化炭
化水素系溶媒を使用する場合は比較的低温（−５
℃〜60℃）で実施するのが好ましい。
(b) 法
(a)法で得た化合物〔―ａ〕の加水分解反応
は、適当な溶媒中、酸またはアルカリを作用させ
ることにより実施することができるが、とりわけ
アルカリを用いて実施するのが好ましい。酸とし
ては、例えば塩酸、硫酸などの鉱酸を用いること
ができ、またアルカリの例としては、たとえば水
酸化ナトリウム、水酸化カリウムなどの水酸化ア
ルカリ金属を好適に用いることができる。溶媒と
しては例えば水、アルカノール（例えばメタノー
ル、エタノール、プロパノール等）、テトラヒド
ロフラン、ジオキサンもしくはこれらの混合溶媒
を使用することができる。反応は、０℃〜100℃、
とくに10℃〜30℃で実施するのが好ましい。
(c) 法
(b)法で得た化合物〔Ｉ―ｂ〕のエステル化反応
は化合物〔―ｂ〕のカルボシキル基における反
応性誘導体とR4―OH（但し、R4は前記と同一意
味を有する）で示されるアルカノールとを反応さ
せることにより実施することができる。本反応に
用いられる反応性誘導体としては例えば化合物
〔―ｂ〕の酸ハライド、混合酸無水物などを用
いることができるが、特に酸ハライドを用いるの
が適当である。R4―OHで示されるアルカノール
としては、例えばメタノール、エタノール、プロ
パノール、イソプロパノール、ブタノール、イソ
ブタノール、ペンタノール、イソペンタノール、
オクタノール、ラウリルアルコール等を好適に用
いることができる。化合物〔―ｂ〕の酸ハライ
ドを用いる場合は適当な溶媒中脱酸剤の存在下も
しくは非存在下に、R4―OHと反応させることに
より実施することができる。脱酸剤としては、例
えばトリエチルアミン、トリブチルアミン、ピリ
ジンの如き有機塩基、あるいは炭酸カリウム、炭
酸ナトリウム、炭酸水素ナトリウムの如き無機塩
基を用いることができる。溶媒としては、例えば
塩化メチルン、クロロホルム、四塩化炭素、酢酸
エチル、テトラヒドロフラン、ジオキサン、アセ
トニトリル、ベンゼン、トルエン、ジメチルホル
ムアミドなどを用いることができるが、R4―OH
で示されるアルカノールを過剰に用いる場合には
該アルカノールが溶媒としても役立つため、他の
溶媒を必ずしも用いる必要はない。本反応は−10
℃〜60℃で、とりわけ−10℃〜30℃で実施するの
が好ましい。
尚、上記反応に用いる化合物〔―ｂ〕の酸ハ
ライド（例えば酸クロライド）は遊離カルボン酸
〔―ｂ〕またはその塩（例えばアルカリ金属塩、
第３級アミン塩など〕を適当な溶媒中ハロゲン化
剤で処理することにより得られる。ハロゲン化剤
としては例えばチオニルクロリド、オキザリルク
ロリド、オキシ塩化リン、三塩化リン、三臭化リ
ン、五塩化リンなどを好適に用いることができ
る。アルカリ金属塩としては例えばナトリウム
塩、カリウム塩などを用いることができ、第３級
アミン塩の例としてはたとえばトリエチルアミン
塩、トリブチルアミン塩などを用いることができ
る。溶媒としては例えばベンゼン、トルエン、ク
ロロホルム、ジオキサン、テトラヒドロフラン、
アセトニトリルなどを用いることができる。ハロ
ゲン化剤を過剰に用いる場合には該ハロゲン化剤
が溶媒としても役立つため他の溶媒の使用は必ず
しも必要でない。本ハロゲン化反応は−10℃〜60
℃で実施するのが好ましい。
また、化合物〔―ｂ〕のエステル化反応は、
適当な溶媒中脱水剤及び塩基の存在下、R4―OH
（但し、R4は前記と同一意味を有する）で示され
るアルカノールと反応させることによつても実施
することができる。脱水剤としては例えばヨウ化
２―クロロ―１―メチルピリジニウム、ヨウ化２
―ブロモ―１―メチルピリジニウムなどを好適に
用いることができる。塩基としては例えばトリエ
チルアミン、トリブチルアミン、ピリジンなどを
使用することができる。溶媒としては、例えばテ
トラヒドロフラン、ジオキサン、アセトニトリ
ル、トルエン、ベンゼン、クロロホルムなどを用
いることができる。本反応は０℃〜30℃で実施す
るのが好ましい。
さらに、化合物〔―ｂ〕のエステル化反応
は、化合物〔―ｂ〕とR4―OH（但し、R4は前
記と同一意味を有する）で示されるアルカノール
を酸（例えばｐ・トルエンスルホン酸、硫酸な
ど）の存在下、50℃〜100℃で反応させるか、あ
るいは化合物〔―ｂ〕を適当な溶媒（例えばテ
トラヒドロフラン、ジオキサン、クロロホルム、
ベンゼン、トルエン、酢酸エチル、ジメチルホル
ムアミドなど）中、無機塩基（例えば炭酸カリウ
ム、炭酸ナトリウムなど）または第３級アミン
（例えばトリエチルアミン、トリブチルアミンな
ど）の存在下、アルキルハライド（例えばヨウ化
メチル、ヨウ化エチル、臭化プロピル、臭化ブチ
ル、塩化ベンチル、臭化ラウリルなど）と10℃〜
100℃で反応させることによつても実施すること
ができる。
かくして得られる本発明化合物〔〕におい
て、R2で示される基が水素原子である場合には
該化合物〔〕を医薬として使用する場合、遊離
カルボン酸の形でも使用できるが、その薬理的に
許容しうる塩の形で使用することもできる。この
ような塩としては、例えば、ナトリウム塩、カリ
ウム塩の如きアルカリ金属塩、カルシウム塩、マ
グネシウム塩の如きアルカリ土類金属塩、リジ
ン、オルニチン、アルギニン、ヒスチジンの如き
塩基性アミノ酸との塩あるいはアンモニウム塩な
どが適している。
本発明の化合物〔〕を医薬として用いる場
合、経口的にも非経口的にも投与することができ
る。
本発明の化合物〔〕を経口的に投与する場合
は、例えば錠剤、散剤、カプセル剤、顆粒剤等と
することができ、それらは慣用の賦形剤、例えば
炭酸カルシウム、リン酸カルシウム、とうもろこ
しでんぷん、ジヤガイモでんぷん、砂糖、ラクト
ース、タルク、ステアリン酸マグネシウム等を含
有していてもよい。また、水性もしくは油性けん
濁剤、溶液、シロツプ、エリキシル剤等の液剤と
してもよい。さらに、非経口的に投与する場合
は、例えば注射用製剤、坐剤などとし、注射用製
剤とする場合は溶液又はけん濁液のような形態で
与えられ、それらは注射用蒸留水、精油（例え
ば、ピーナツツ油、とうもろこし油）或いは非水
溶媒（例えば、ポリエチレングリコール、ポリプ
ロピレンングリコール、ラノリン、ココナツツ油
等）を含有していてもよい。
尚、本発明の原料化合物〔〕も新規化合物で
あり、例えば、下記反応式で示される方法により
製造することができる。
（但し、上記式中R5はエステル残基を表わし、
X1はハロゲン原子または基
The present invention relates to a novel furyl oxazolyl acetic acid derivative and a method for producing the same, more specifically, the general formula (However, R 1 is an alkyl group, a cycloalkyl group, a phenyl group, or a phenyl group having 1 to 2 substituents selected from an alkyl group, an alkoxy group, and a halogen atom, and R 2 is a hydrogen atom. The present invention relates to a furyloxazolyl acetic acid derivative or a pharmacologically acceptable salt thereof, and a method for producing the same. The compound [ ] of the present invention has an excellent serum cholesterol-lowering effect and serum triglyceride-lowering effect, and is a useful pharmaceutical compound as an antilipemic agent.
Moreover, the compound of the present invention [ ] has the characteristics of having few side effects such as liver dysfunction and also having a platelet aggregation inhibiting effect, which is a preferable accompanying effect for an antilipemic agent. Examples of the compounds of the present invention include general formula [] in which R 1 is a methyl group, an ethyl group, a propyl group,
Alkyl groups having 1 to 6 carbon atoms such as isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, cyclopentyl group,
A cycloalkyl group with 5 to 6 carbon atoms, such as a cyclohexyl group, or a phenyl group, or a cycloalkyl group with 1 carbon number, such as a methyl group or an ethyl group, on a benzene ring.
~2 alkyl groups, alkoxy groups having 1 to 2 carbon atoms such as methoxy groups, and ethoxy groups, and chlorine;
A phenyl group having 1 to 2 substituents selected from halogen atoms such as fluorine, bromine, and iodine, and R 2 is a hydrogen atom, or a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group,
Examples include compounds which are alkyl groups having 1 to 12 carbon atoms such as octyl group and lauryl group. Among these, preferred compounds include general formula [] in which R 1 is a methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, cyclohexyl group, phenyl group, 4-chlorophenyl group, 4-fluorophenyl group. , 4-methylphenyl group, 4-
Examples include methoxyphenyl group, 3,4-dichlorophenyl group, etc., and compounds in which R 2 is a hydrogen atom or an ethyl group. Particularly preferred compounds include those in which R 1 is an n-butyl group, 4-chlorophenyl group, 4-fluorophenyl group, etc.
Examples include compounds in which R 2 is a hydrogen atom or an ethyl group. According to the present invention, the compound [] has (a) the general formula (However, R 3 represents an alkyl group, and R 1 has the same meaning as above.) The 3-acylaminopropionic acid derivative represented by the formula (However, R 1 and R 3 have the same meanings as above) or (b) by hydrolyzing the compound [-a] obtained by the above method (a). general formula (However, R 1 has the same meaning as above) or (c) esterify the compound [-b] obtained by the above method (b) to obtain the general formula (However, R 4 represents an alkyl group, and R 1 has the same meaning as above.) It can be produced by using a furyl oxazolyl acetate derivative as shown below. Hereinafter, the reaction of the present invention will be explained in detail. (a) Method The dehydration ring-closing reaction of compound [] can be carried out by reacting with a dehydrating agent in a suitable solvent. As the dehydrating agent, for example, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, phosgene, phosphorus pentoxide, etc. can be used. In addition, as a catalytic dehydrating agent,
P-toluenesulfonic acid, sulfuric acid, etc. can also be suitably used. Examples of solvents used include chloroform, methylene chloride, carbon tetrachloride, benzene, toluene, xylene, tetrahydrofuran, and dimethylformamide. This reaction starts at -5℃
130℃, especially when using a halogenated hydrocarbon solvent as a reaction solvent, at a relatively low temperature (-5℃)
℃~60℃). (b) Method The hydrolysis reaction of the compound [-a] obtained by method (a) can be carried out by reacting with an acid or an alkali in a suitable solvent, but in particular it can be carried out using an alkali. is preferred. As the acid, a mineral acid such as hydrochloric acid or sulfuric acid can be used, and as an example of the alkali, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide can be suitably used. As the solvent, for example, water, alkanol (eg, methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane, or a mixed solvent thereof can be used. The reaction is carried out at 0°C to 100°C,
It is particularly preferable to carry out the reaction at a temperature of 10°C to 30°C. (c) Method The esterification reaction of the compound [I-b] obtained by method (b) is carried out using a reactive derivative in the carboxyl group of the compound [-b] and R 4 -OH (where R 4 has the same meaning as above). It can be carried out by reacting with an alkanol shown in (having). As the reactive derivative used in this reaction, for example, an acid halide or a mixed acid anhydride of the compound [-b] can be used, but it is particularly suitable to use an acid halide. Examples of the alkanol represented by R 4 -OH include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isopentanol,
Octanol, lauryl alcohol, etc. can be suitably used. When using the acid halide of compound [-b], the reaction can be carried out by reacting it with R 4 --OH in a suitable solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, for example, organic bases such as triethylamine, tributylamine, and pyridine, or inorganic bases such as potassium carbonate, sodium carbonate, and sodium bicarbonate can be used. As the solvent, for example, methyl chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, dimethylformamide, etc. can be used, but R 4 -OH
When the alkanol represented by is used in excess, the alkanol also serves as a solvent, so it is not necessarily necessary to use other solvents. This reaction is −10
Preference is given to carrying out the reaction at temperatures between 60°C and 60°C, especially between -10°C and 30°C. Note that the acid halide (e.g., acid chloride) of the compound [-b] used in the above reaction may be the free carboxylic acid [-b] or its salt (e.g., alkali metal salt,
tertiary amine salt, etc.] with a halogenating agent in an appropriate solvent. As the halogenating agent, for example, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc. can be suitably used. Examples of the alkali metal salts that can be used include sodium salts and potassium salts, and examples of the tertiary amine salts that can be used include triethylamine salts and tributylamine salts. Examples of solvents include benzene, toluene, chloroform, dioxane, tetrahydrofuran,
Acetonitrile or the like can be used. When the halogenating agent is used in excess, the halogenating agent also serves as a solvent, so the use of other solvents is not necessarily necessary. This halogenation reaction ranges from -10℃ to 60℃.
Preferably, it is carried out at .degree. In addition, the esterification reaction of compound [-b] is
In the presence of a dehydrating agent and a base in a suitable solvent, R 4 -OH
(However, R 4 has the same meaning as above.) It can also be carried out by reacting with an alkanol represented by the following. Examples of dehydrating agents include 2-chloro-1-methylpyridinium iodide and 2-chloro-1-methylpyridinium iodide.
-Bromo-1-methylpyridinium and the like can be suitably used. As the base, for example, triethylamine, tributylamine, pyridine, etc. can be used. As the solvent, for example, tetrahydrofuran, dioxane, acetonitrile, toluene, benzene, chloroform, etc. can be used. This reaction is preferably carried out at 0°C to 30°C. Furthermore, in the esterification reaction of compound [-b], compound [-b] and an alkanol represented by R 4 --OH (where R 4 has the same meaning as above) are combined with an acid (for example, p-toluenesulfonic acid, sulfuric acid, etc.) at 50°C to 100°C, or compound [-b] is reacted in the presence of a suitable solvent (such as tetrahydrofuran, dioxane, chloroform,
Alkyl halides (e.g. methyl iodide, iodide, ethyl chloride, propyl bromide, butyl bromide, benzyl chloride, lauryl bromide, etc.) and from 10°C
It can also be carried out by reacting at 100°C. In the thus obtained compound of the present invention [], when the group represented by R 2 is a hydrogen atom, when the compound [] is used as a medicine, it can be used in the form of a free carboxylic acid; It can also be used in the form of a salt. Examples of such salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with basic amino acids such as lysine, ornithine, arginine, and histidine, or ammonium salts. Salt is suitable. When the compound of the present invention [ ] is used as a medicine, it can be administered either orally or parenterally. When the compound of the present invention [ ] is administered orally, it can be administered in the form of tablets, powders, capsules, granules, etc., which may be prepared using conventional excipients such as calcium carbonate, calcium phosphate, corn starch, and potato. It may contain starch, sugar, lactose, talc, magnesium stearate, etc. It may also be used as a liquid preparation such as an aqueous or oily suspension, solution, syrup, or elixir. Furthermore, when administering parenterally, it is given in the form of an injection preparation, suppository, etc., and when it is an injection preparation, it is given in the form of a solution or suspension. For example, it may contain peanut oil, corn oil) or a non-aqueous solvent (for example, polyethylene glycol, polypropylene glycol, lanolin, coconut oil, etc.). Note that the raw material compound [] of the present invention is also a new compound, and can be produced, for example, by the method shown in the following reaction formula. (However, in the above formula, R 5 represents an ester residue,
X 1 is a halogen atom or group
【式】を表
わし、X2およびX3はハロゲン原子を表わし、R1
およびR3は前記と同一意味を有する）
すなわち、２―または３―フリルカルボン酸類
化合物〔〕（例えば酸ハライド、酸無水物）と
イソシアノ酢酸エステル〔〕とを適当な溶媒
（例えばテトラヒドロフラン、ジオキサン、ジメ
チルホルムアミドなど）中、塩基（例えばトリエ
チルアミン、第三級ブトキシカリウム、１，８―
ジアザビシクロ〔５，４，０〕ウンデセン―７）
の存在下約−50℃〜50℃で反応させることにより
オキサゾールカルボン酸類化合物〔〕を得、該
化合物〔〕を水酸化ナトリウムの如き水酸化ア
ルカリでケン化した（約20℃〜50℃）後中和して
オキサゾールカルボン酸〔〕を得、このカルボ
ン酸を鉱酸（例えば2N塩酸メタノール）で処理
する（約40℃〜80℃）ことによりアミノケトン化
合物〔〕を得る。また、この化合物〔〕は化
合物〔〕を例えば4N塩酸等の鉱酸と約50℃〜
80℃に加熱するなどの酸加水分解することによつ
ても得ることができる。次いで〔〕を水および
適当な溶媒（例えば酢酸エチル、ベンゼンなど）
中、塩基（例えば水酸化アルカリ金属、炭酸アル
カリ金属）の存在下酸ハライド類化合物〔〕と
冷時反応させることによりＮ―アシルアミン類化
合物〔〕を得、さらに該化合物〔〕とハロゲ
ノ酢酸エステル〔〕とを適当な溶媒（例えばテ
トラヒドロフラン、ジオキサン、ジメチルホルム
アミド、ジメチルスルホキシド、アセトニトリル
など）中、塩基（例えば水酸化ナトリウム、第三
級ブトキシカリウム、アルキルリチウム等）の存
在下に約−50℃〜30℃で反応させることにより、
３―アシルアミノプロピオン酸誘導体〔〕を得
ることができる。
実験例 １
（脂質低下作用）
検体をラツト用粉末飼料に混合し（検体含量：
50mg％）、該混合物をSD系雄性ラツト（体重：
120〜140g、１群５匹）に１周間自由摂取させた
後、エーテル麻酔下に尾部より採血し、その後速
やかに肝臓を摘出して肝重量を測定した。一方、
採取した血液を用いて血清コレステロール量をザ
ツク法（アメリカン・ジヤーナル・オブ・クリニ
カル・パソロジイー，24：pp1307（1954））によ
り、また血清トリグリセリド量をバン ハンデル
ーチルバースミツト法（ジヤナル・オブ・ラボラ
トリー・アンド・クリニカル・メデイシン，50：
pp152（1957））により測定した。これらの結果か
ら下式により血清コレステロール及びトリグリセ
リド低下率及び肝相対重量増加率を求めた。血清
脂質低下作用の結果は下記第１表の通りである。
また、肝相対重量増加率については、クロフイブ
レートは12％であつたが本発明化合物群はいずれ
も０％であつた。[Formula] is represented, X 2 and X 3 represent halogen atoms, and R 1
and R 3 have the same meanings as above) In other words, a 2- or 3-furylcarboxylic acid compound [ ] (e.g., acid halide, acid anhydride) and isocyanoacetate [ ] are mixed in a suitable solvent (e.g., tetrahydrofuran, dioxane, base (e.g. triethylamine, potassium tert-butoxy, 1,8-
Diazabicyclo[5,4,0]undecene-7)
Oxazolecarboxylic acid compound [ ] is obtained by reacting at about -50°C to 50°C in the presence of The oxazole carboxylic acid [ ] is obtained by neutralization, and the aminoketone compound [ ] is obtained by treating this carboxylic acid with a mineral acid (for example, 2N hydrochloric acid methanol) (about 40°C to 80°C). In addition, this compound [] can be mixed with a mineral acid such as 4N hydrochloric acid at about 50°C or more.
It can also be obtained by acid hydrolysis, such as heating to 80°C. Then [ ] is dissolved in water and a suitable solvent (e.g. ethyl acetate, benzene, etc.)
In the presence of a base (e.g., alkali metal hydroxide, alkali metal carbonate), an N-acylamine compound [] is obtained by reacting it with an acid halide compound [] in the presence of a base (for example, an alkali metal hydroxide, an alkali metal carbonate), and then the compound [] and a halogenoacetic acid ester [] are obtained. ] in a suitable solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.) in the presence of a base (e.g., sodium hydroxide, potassium tert-butoxy, alkyl lithium, etc.) at about -50°C to 30°C. By reacting at °C,
A 3-acylaminopropionic acid derivative [] can be obtained. Experimental example 1 (lipid-lowering effect) The sample was mixed with powdered feed for rats (sample content:
50mg%), and the mixture was administered to SD male rats (body weight:
After feeding (120 to 140 g, 5 animals per group) ad libitum for one week, blood was collected from the tail under ether anesthesia, and the liver was immediately removed and the liver weight was measured. on the other hand,
Using the collected blood, serum cholesterol levels were measured using the Zatsk method (American Journal of Clinical Pathology, 24 : pp1307 (1954)), and serum triglyceride levels were measured using the Van Handel-Tilversmit method (Journal of Laboratory Medicine). and clinical medicine, 50 :
pp152 (1957)). From these results, serum cholesterol and triglyceride reduction rates and liver relative weight increase rates were determined using the following formulas. The results of the serum lipid lowering effect are shown in Table 1 below.
Furthermore, the relative liver weight increase rate was 12% for clofibrate, but 0% for all compounds of the present invention.
【表】【table】
【表】
実験例 ２
（血小板凝集抑制作用）
エーテル麻酔したSD系雄性ラツト（体重：250
〜300g）の腹部大動脈より血液を採取し、直ち
に該血液９容を3.8％クエン酸三ナトリウム水溶
液１容と混和した後、遠心分離（500×ｇ，５分
間）し、その上層を採取して多血小板血漿
（PRP）を調製した。残存血液を更に遠心分離
（1000×ｇ，10分間）し、その上層を採取して乏
血小板血漿（PPP）を調製した。PRPの血小板
数はPPPで希釈して８〜10×105cells／mm2に調整
した。凝集測定計（シエンコ社，DP―247―Ｄ
型）のセルに上記で調製したPRP200μlと検体溶
液25μlを取り、37℃，1100rpmで２分間前培養し
た後、ホルムセンらの方法〔ビオキミカ・エ・ビ
オフイジカ・アクタ，186，254（1969）〕で調製し
たコラーゲンけん濁液（100μg／ml）25μlを加え
て血小板凝集を起こさせた。凝集能の測定はボー
ンの方法〔ネイチヤー、194，927（1962）〕に従つ
て行ない、下式により血小板凝集抑制率を求めて
抑制率が10％未満のものを（−），10％以上のも
のを（＋）と判定した。その結果は下記第２表の
通りである。
抑制率＝〔１−検体添加時の凝集率／検体無添加時の
凝集率〕×100[Table] Experimental example 2 (inhibitory effect on platelet aggregation) SD male rats anesthetized with ether (body weight: 250
Blood was collected from the abdominal aorta of ~300 g), immediately mixed with 1 volume of 3.8% trisodium citrate aqueous solution, centrifuged (500 x g, 5 minutes), and the upper layer was collected. Platelet rich plasma (PRP) was prepared. The remaining blood was further centrifuged (1000×g, 10 minutes), and the upper layer was collected to prepare platelet-poor plasma (PPP). The platelet count of PRP was adjusted to 8 to 10×10 5 cells/mm 2 by diluting with PPP. Agglomeration meter (Cienco, DP-247-D
200 μl of the PRP prepared above and 25 μl of the sample solution were placed in a cell of type 1), preincubated at 37°C and 1100 rpm for 2 minutes, and then incubated using the method of Holmsen et al. 25 μl of the prepared collagen suspension (100 μg/ml) was added to cause platelet aggregation. The aggregation ability was measured according to the method of Born [Nature, 194 , 927 (1962)], and the inhibition rate of platelet aggregation was calculated using the following formula. The item was judged as (+). The results are shown in Table 2 below. Suppression rate = [1-Agglutination rate when adding sample/Agglutination rate when no sample is added] x 100
【表】【table】
【表】
実施例 １
３―（４―クロロベンゾイルアミノ）―３―
（２―フリルカルボニル）プロピオン酸エチル
37gをクロロホルム150mlにとかし、該溶液にオ
キシ塩化リン64.9gを室温で滴下し、60℃〜70℃
で８時間かくはん還流する。反応終了後、混合物
を氷水中に注入し、炭酸水素ナトリウムで液性を
中性とし、次いで酢酸エチルで抽出する。抽出層
を水洗乾燥後、活性炭処理し、減圧下に溶媒を留
去する。残査をジイソプロピルエーテルで結晶化
した後、該結晶をエタノールから再結晶すること
により、２―〔２―（４―クロロフエニル）―５
―（２―フリル）―４―オキサゾリル〕酢酸エチ
ル30gを得る。収率85.5％
m.p.105℃〜106℃
IRνnujol nax（cm-1）：1723，1600
実施例 ２
３―アセチルアミノ―３―（２―フリルカルボ
ニル）プロピオン酸エチル1.6g、クロロホルム20
mlおよびオキシ塩化リン4.8gより、実施例１と同
様に反応し後処理し、得られる残査をシリカゲル
カラムクロマトグラフイーに付し（溶媒；ジイソ
プロピルエーテル：クロロホルム＝１：１）、溶
出したフラクシヨンを減圧下に濃縮することによ
り、２―〔２―メチル―５―（２―フリル）―４
―オキサゾリル〕酢酸エチル1.2gをシロツプとし
て得る。収率80.0％
IRνfilm nax（cm-1）：3130，1735
実施例 ３
３―ペンタノイルアミノ―３―（２―フリルカ
ルボニル）プロピオン酸エチル5.0gの塩化メチレ
ン50ml溶液に五酸化リン10gとケイソウ±10gの
混合物を加え、６時間かくはん還流する。反応
後、実施例２と同様に処理することにより、２―
〔２―ｎ・ブチル―５―（２―フリル）―４―オ
キサゾリル〕酢酸エチル4.0gをシロツプとして得
る。収率85.1％
IRνfilm nax（cm-1）：3120，1735
実施例 ４
３―（４―メトキシベンゾイルアミノ）―３―
（２―フリルカルボニル）プロピオン酸エチル
10gのクロロホルム60ml溶液に、チオニルクロリ
ド15mlを室温で滴下し、次いで60℃〜70℃で６時
間かくはん還流する。反応終了後、実施例１と同
様処理することにより、２―〔２―（４―メトキ
シフエニル）―５―（２―フリル）―４―オキサ
ゾリル〕酢酸エチル3.0g得る。
収率31.6％
m.p.64℃〜66℃
IRνnujol nax（cm-1）：3130，1730
実施例 ５〜12
実施例１〜２と同様にして以下の化合物を製造
した。
[Table] Example 1 3-(4-chlorobenzoylamino)-3-
(2-furylcarbonyl)ethyl propionate
Dissolve 37 g in 150 ml of chloroform, add 64.9 g of phosphorus oxychloride dropwise to the solution at room temperature, and heat at 60°C to 70°C.
Stir and reflux for 8 hours. After the reaction is complete, the mixture is poured into ice water, made neutral with sodium bicarbonate, and then extracted with ethyl acetate. The extracted layer is washed with water, dried, treated with activated carbon, and the solvent is distilled off under reduced pressure. After crystallizing the residue from diisopropyl ether, the crystals were recrystallized from ethanol to give 2-[2-(4-chlorophenyl)-5
Obtain 30 g of ethyl -(2-furyl)-4-oxazolyl]acetate. Yield 85.5% mp105℃～106℃ IRν nujol nax (cm -1 ): 1723, 1600 Example 2 Ethyl 3-acetylamino-3-(2-furylcarbonyl)propionate 1.6g, chloroform 20
ml and 4.8 g of phosphorus oxychloride were reacted and post-treated in the same manner as in Example 1, and the resulting residue was subjected to silica gel column chromatography (solvent: diisopropyl ether:chloroform = 1:1) to obtain the eluted fraction. By concentrating under reduced pressure, 2-[2-methyl-5-(2-furyl)-4
- Oxazolyl] Obtain 1.2 g of ethyl acetate as syrup. Yield 80.0% IRν film nax (cm -1 ): 3130, 1735 Example 3 A solution of 5.0 g of ethyl 3-pentanoylamino-3-(2-furylcarbonyl)propionate in 50 ml of methylene chloride was added with 10 g of phosphorus pentoxide and diatom. Add ±10 g of the mixture and stir and reflux for 6 hours. After the reaction, 2-
4.0 g of ethyl [2-n-butyl-5-(2-furyl)-4-oxazolyl] acetate is obtained as syrup. Yield 85.1% IRν film nax (cm -1 ): 3120, 1735 Example 4 3-(4-methoxybenzoylamino)-3-
(2-furylcarbonyl)ethyl propionate
15 ml of thionyl chloride is added dropwise to a solution of 10 g in 60 ml of chloroform at room temperature, and the mixture is then stirred and refluxed at 60°C to 70°C for 6 hours. After the reaction was completed, 3.0 g of ethyl 2-[2-(4-methoxyphenyl)-5-(2-furyl)-4-oxazolyl]acetate was obtained by the same treatment as in Example 1. Yield 31.6% mp64°C to 66°C IRv nujol nax (cm -1 ): 3130, 1730 Examples 5 to 12 The following compounds were produced in the same manner as Examples 1 to 2.
【表】
実施例 14
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―４―オキサゾリル〕酢酸エチル1.0g
に、５℃〜10℃で水酸化カリウム0.4gのメタノー
ル30ml溶液を加え、次いで室温で10時間かくはん
する。析出する結晶をろ取し、エーテルで洗浄し
乾燥することにより、２―〔２―（４―クロロフ
エニル）―５―（２―フリル）―４―オキサゾリ
ル〕酢酸カリウム0.85gを得る。
収率80.2％
m.p.250℃以上
IRνnujol nax（cm-1）：1610
実施例 15
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―４―オキサゾリル〕酢酸カリウム塩
0.85gを水にとかし、塩酸を加えて液性を酸性と
し、析出する結晶をろ取する。該結晶をエタノー
ルから再結晶することにより、２―〔２―（４―
クロロフエニル）―５―（２―フリル）―４―オ
キサゾリル〕酢酸0.69gを得る。
収率90.9％
m.p.191℃〜194℃（分解）
IRνnujol nax（cm-1）：1720
実施例 16
２―〔２―フエニル―５―（２―フリル）―４
―オキサゾリル〕酢酸エチル3.5gをメタノール50
mlと水10mlとの混液にとかし、これに水酸化ナト
リウム1.2gを加え室温で10時間かくはんする。反
応終了後、混合物を減圧下に濃縮してメタノール
を留去する。残査に水を加え、ついで濃塩酸で液
性を酸性（PH２）とし、酢酸エチルで抽出する。
抽出層を水で洗浄し、乾燥後減圧下に溶媒を留去
する。残査をエタノールから再結晶することによ
り、２―〔２―フエニル―５―（２―フリル）―
４―オキサゾリル〕酢酸2.5gを得る。収率78.1％
m.p.175℃〜177℃
IRνnujol nax（cm-1）：3100，1690
実施例 17〜25
実施例16と同様にして以下の化合物を製造し
た。
[Table] Example 14 2-[2-(4-chlorophenyl)-5-(2
-furyl)-4-oxazolyl]ethyl acetate 1.0g
A solution of 0.4 g of potassium hydroxide in 30 ml of methanol is added to the mixture at 5°C to 10°C, and then stirred at room temperature for 10 hours. The precipitated crystals are collected by filtration, washed with ether, and dried to obtain 0.85 g of potassium 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate. Yield 80.2% mp250℃ or higher IRν nujol nax (cm -1 ): 1610 Example 15 2-[2-(4-chlorophenyl)-5-(2
-furyl)-4-oxazolyl] potassium acetate salt
Dissolve 0.85g in water, add hydrochloric acid to make the liquid acidic, and filter out the precipitated crystals. By recrystallizing the crystals from ethanol, 2-[2-(4-
0.69 g of chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid is obtained. Yield 90.9% mp191℃~194℃ (decomposition) IRν nujol nax (cm -1 ): 1720 Example 16 2-[2-phenyl-5-(2-furyl)-4
-Oxazolyl] 3.5g of ethyl acetate to 50% of methanol
ml and 10 ml of water, add 1.2 g of sodium hydroxide, and stir at room temperature for 10 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove methanol. Water is added to the residue, the liquid is made acidic (PH2) with concentrated hydrochloric acid, and extracted with ethyl acetate.
The extracted layer is washed with water, dried, and the solvent is distilled off under reduced pressure. By recrystallizing the residue from ethanol, 2-[2-phenyl-5-(2-furyl)-
2.5 g of 4-oxazolyl]acetic acid is obtained. Yield 78.1% mp 175°C to 177°C IRν nujol nax (cm -1 ): 3100, 1690 Examples 17 to 25 The following compounds were produced in the same manner as in Example 16.
【表】【table】
【表】
実施例 26
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―４―オキサゾリル〕酢酸1.0g、ヨウ
化２―クロロ―１―メチルピリジニウム1.0gおよ
びイソプロパノール0.24gをテトラヒドロフラン
30mlにとかし、これにトリエチルアミン0.8gを滴
下し、ついで室温で10時間かくはんする。反応混
合物に水を加えた後、減圧下にテトラヒドロフラ
ンを留去し、残査を酢酸エチルで抽出する。抽出
層を20％クエン酸水溶液、炭酸水素ナトリウム水
ついで水で洗浄し、乾燥する。減圧下に溶媒を留
去し、残査をエタノールから再結晶することによ
り、２―〔２―（４―クロロフエニル）―５―
（２―フリル）―４―オキサゾリル〕酢酸イソプ
ロピル0.5gを得る。収率43.6％
m.p.96℃〜97℃
IRνnujol nax（cm-1）：3110，1725
実施例 27
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―オキサゾリル〕酢酸2.0g、ヨウ化２
―クロロ―１―メチルピリジニウム2.02g、ラウ
リルアルコール1.47g、トリエチルアミン1.60gお
よびテトラヒドロフラン60mlを用い、実施例26と
同様処理することにより、２―〔２―（４―クロ
ロフエニル）―５―（２―フリル）―４―オキサ
ゾリル〕酢酸ラウリル2.4gを得る。収率77.4％
m.p.69.5℃〜71℃
IRνnujol nax（cm-1）：3050，1735
実施例 28
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―４―オキサゾリル〕酢酸2.0gのクロ
ロホルム20ml溶液にチオニルクロリド2.0gを室温
下に加えた後、混合物を３時間かくはん還流す
る。冷後、反応液にｎ・ブタノール0.6gを加え、
同温度で６時間かくはんする。反応終了後、減圧
下に溶媒を留去し、残査を酢酸エチルで抽出す
る。抽出層を炭酸水素ナトリウム水溶液ついで水
で洗浄し、乾燥する。溶媒を減圧留去し、残査を
エタノールから再結晶することにより、２―〔２
―（４―クロロフエニル）―５―（２―フリル）
―４―オキサゾリル〕酢酸ｎ・ブチル1.5gを得
る。収率62.3％
m.p.96℃〜97℃
IRνnujol nax（cm-1）：3050，1730
実施例 29
２―〔２―（４―クロロフエニル）―５―（２
―フリル）―４―オキサゾリル〕酢酸1.5gおよび
ｎ・ヘプチルブロミド1.0gのジメチルホルムアミ
ド25ml溶液にトリエチルアミン0.92gを室温で滴
下し、ついで30℃〜40℃で４時間かくはんする。
反応物を水中に注ぎ、ジエチルエーテル：酢酸エ
チル（１：１）で抽出する。抽出層を実施例26と
同様処理することにより、２―〔２―（４―クロ
ロフエニル）―５―（２―フリル）―４―オキサ
ゾリル〕酢酸ｎ・ヘプチル0.85gを得る。収率
42.7％
m.p.69℃〜70℃
IRνnujol nax（cm-1）：3050，1735
参考例 １
(1) （２―フリルカルボニル）メチルアミン塩酸
塩10g、炭酸水素ナトリウム12.5g、酢酸エチル
200mlおよび水100mlの混合物に、かくはん下４
―クロロベンゾイルクロリド12.0gを10℃以下
で滴下する。さらに室温で３時間かくはん後、
酢酸エチル層を分取し、これを水洗後乾燥す
る。溶媒を減圧留去することにより、Ｎ―４―
クロロベンゾイル―（２―フリルカルボニル）
メチルアミン16.0gを得る。収率98.2％
m.p.138℃〜139℃
IRνnujol nax（cm-1）：3400，1680，1660，1595
(2) Ｎ―４―クロロベンゾイル―（２―フリルカ
ルボニル）メチルアミン40gのジメチルホルム
アミド160ml溶液に、かくはん下61％水素化ナ
トリウム7.2gを−50℃〜−40℃で加え、さらに
５分間かくはんする。ついで反応混合物にモノ
ブロモ酢酸エチル27.7gを同温度で加え、１時
間かくはんする。反応温度を徐々に０℃付近ま
で上昇さて、さらに１時間かくはんする。反応
終了後、混合物を酢酸で中和し、水を加え、酢
酸エチルで抽出する。抽出層を炭酸水素ナトリ
ウム、ついで水で洗浄し、乾燥後、溶媒を減圧
下に留去する。残査をイソプロピルエーテル―
ｎ・ヘキサン混液から結晶化することにより、
３―（４―クロロベンゾイルアミン）―３―
（２―フリルカルボニル）プロピオン酸エチル
37.0gを得る。収率70％
m.p.100℃〜102℃
IRνnujol nax（cm-1）：3300，3100，1738，1680，
1630，1595
参考例 ２
(1) 第三級ブトキシカリウム6.0gをテトラヒドロ
フラン60mlに溶解し、−50℃でα―イソシアノ
酢酸メチル4.4gをかくはん下に滴下する。同温
度で１時間かくはんを続けたのち、これに３―
フランカルボン酸クロリド5.8gをかくはん下同
温度で滴下する。さらに２時間かくはん後、反
応液に酢酸を加えて液性をPH３〜４とし、混合
物を減圧下に濃縮して溶媒を留去する。残査を
酢酸エチルで抽出し、抽出層を水および炭酸水
素ナトリウム液で洗浄し、乾燥後溶媒を減圧下
に留去する残査をイソプロピルエーテルで洗浄
することにより、５―（３―フリル）オキサゾ
ール―４―カルボン酸メチル6.5gを得る。収率
75.4％
m.p.87℃〜88℃
IRνnujol nax（cm-1）：3120，1695
(2) ５―（３―フリル）オキサゾール―４―カル
ボン酸メチル3gおよび85％水酸化カリウム2.6g
をメタノール100mlにとかし、一夜室温でかく
はんする。反応液よりメタノールを減圧下に留
去し、残査に希塩酸を加えて液性を酸性とな
し、析出する結晶をろ取し、冷水で洗浄乾燥す
ることにより、５―（３―フリル）オキサゾー
ル―４―カルボン酸2.6gを得る。収率93.7％
m.p.189℃〜191℃
IRνnujol nax（cm-1）：3110，1700，1600
(3) ５―（３―フリル）オキサゾール―４―カル
ボン酸3.0gおよび2N塩酸50mlの混合物を40℃
〜50℃で6.5時間かくはんする。反応物を減圧
濃縮し、残査にアセトンを加えて結晶化し、ろ
取することにより、（３―フリルボニル）メチ
ルアミン・塩酸塩2.2gを得る。収率80％
m.p.196℃〜198℃
IRνnujol nax（cm-1）：3110，1680，1560
(4) （３―フリルカルボニル）メチルアミン・塩
酸塩5g、炭酸水素ナトリウム6.0g、４―クロロ
ベンゾイルクロリド6.0g、酢酸エチル100mlお
よび水50mlを用い、参考例１―(1)と同様処理す
ることにより、Ｎ―４―クロロベンゾイル―
（３―フリルカルボニル）メチルアミン8.2gを
得る。収率100％
m.p.152℃〜154℃
IRνnujol nax（cm-1）：3350，3110，1675，1635，
1595
(5) Ｎ―４―クロロベンゾイル―（３―フリルカ
ルボニル）メチルアミン8.3g，61％水素化ナト
リウム1.5gおよびモノブロモ酢酸エチル5.8gを
用い、参考例１―(2)と同様処理することによ
り、３―（４―クロロベンゾイルアミノ）―３
―（３―フリルカルボニル）プロピオン酸エチ
ル8.5gを得る。収率77.3％
m.p.93℃〜95℃（分解）
IRνnujol nax（cm-1）：3340，3100，1705，1670，
1640
参考例１―(1)および１―(2)と同様処理すること
により以下の化合物を製造した。
参考例 ３
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩3.4g、炭酸水素ナトリウム4.4gおよびベン
ゾイルクロリド3.3gより、Ｎ―ベンゾイル―
（２―フリルカルボニル）メチルアミン4.0gを
得る。収率83.3％
m.p.132℃〜133℃
IRνnujol nax（cm-1）：3400，3100，1675，1600
(2) Ｎ―ベンゾイル―（２―フリルカルボニル）
メチルアミン4g，61％水素化ナトリウム0.8gお
よびモノブロモ酢酸エチル3.2gより、３―ベン
ゾイルアミノ―３―（２―フリルカルボニル）
プロピオン酸エチル4.0gを得る。収率72.7％
m.p.75℃〜76℃
IRνnujol nax（cm-1）：3300，1715，1680，1640
参考例 ４
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩23.4g，炭酸水素ナトリウム29.3gおよび４
―フルオロベンゾイルクロリド23.0gより、Ｎ
―４―フルオロベンゾイル―（２―フリルカル
ボニル）メチルアミン24.0gを得る。収率66.8
％
m.p.153℃〜155℃
IRνnujol nax（cm-1）：3410，3100，1680，1655
(2) Ｎ―４―フルオロベンゾイル―（２―フリル
カルボニル）メチルアミン24.0g，61％水素化
ナトリウム4.7gおよびモノブロモ酢酸エチル
18.4gより、３―（４―フルオロベンゾイルア
ミノ）―３―（２―フリルカルボニル）プロピ
オン酸エチル21.0gを得る。収率64.8％
m.p.95.5℃〜97℃
IRνnujol nax（cm-1）：3300，1725，1690，1640，
1600
参考例 ５
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩8.0g、炭酸水素ナトリウム10.5gおよび４
―メチルベンゾイルクロリド9.2gより、Ｎ―４
―メチルベンゾイル（２―フリルカルボニル）
メチルアミン10.0gを得る。収率83.3％
m.p.139℃〜141℃
IRνnujol nax（cm-1）：3300，3140，1690，1640
(2) Ｎ―４―メチルベンゾイル―（２―フリルカ
ルボニル）メチルアミン12.0g，61％水素化ナ
トリウム2.3gおよびモノブロモ酢酸エチル9.1g
より、３―（４―メチルベンゾイルアミノ）―
３―（２―フリルカルボニル）プロピオン酸エ
チル13.9gを得る。収率85.5％
m.p.83.5℃〜84.5℃
IRνnujol nax（cm-1）：3300，3250，1710，1680，
1640，1610
参考例 ６
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩8.0g、炭酸水素ナトリウム10.5gおよび４
―メトキシベンゾイルクロリド10.1gより、Ｎ
―４―メトキシベンゾイル―（２―フリルカル
ボニル）メチルアミン11.0gを得る。収率85.3
％
m.p.114℃〜115℃
IRνnujol nax（cm-1）：3310，3150，1690，，1635
(2) Ｎ―４―メトキシベンゾイル―（２―フリル
カルボニル）メチルアミン11.0g，61％水素化
ナトリウム2.0gおよびモノブロモ酢酸エチル
7.8gより、３―（４―メトキシベンゾイルアミ
ノ）―３―（２―フリルカボニル）プロピオン
酸エチル10.7gを得る。収率72.8％
m.p.104℃〜106℃
IRνnujol nax（cm-1）：3300，1715，1680，1635，
1610
参考例 ７
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩3.2gおよび無水酢酸10mlの酢酸エチル50ml
溶液に、炭酸水素ナトリウム水溶液をかくはん
下、液性がアルカリ性になるまで室温で適下す
る。さらに１時間かくはん後、酢酸エチル層を
分取し、水で洗浄後乾燥する。溶媒を減圧留去
し、残査をイソプロピルエーテルで洗浄するこ
とにより、Ｎ―アセチル―（２―フリルカルボ
ニル）メチルアミン1.5gを得る。収率45.0％
m.p.114℃〜115℃
IRνnujol nax（cm-1）：3380，3090，1670，1655
(2) Ｎ―アセチル―（２―フリルカルボニル）メ
チルアミン2.6g、61％水素化ナトリウム0.74g
およびモノブロモ酢酸エチル2.9gより、３―ア
セチルアミノ―３―（２―フリルカルボニル）
プロピオン酸エチル1.6gを得る。収率41％
m.p.82℃〜84℃
IRνnujol nax（cm-1）：3280，3100，1680，1650
参考例 ８
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩16.0g、炭酸水素ナトリウム20.5gおよびイ
ソブチルクロリド11.4gより、Ｎ―イソブチリ
ル―（２―フリルカルボニル）メチルアミン
13.0gを得る。収率67.0％
m.p.78℃〜80℃
IRνnujol nax（cm-1）：3300，3130，1680，1640
(2) Ｎ―イソブチリル―（２―フリルカルボニ
ル）メチルアミン13.0g，61％水素化ナトリウ
ム3.1gおよびモノブロモ酢酸エチル12.2gより、
３―イソブチリルアミノ―３―（２―フリルカ
ルボニル）プロピオン酸エチル12.0gを得る。
収率64.2％
m.p.65℃〜67℃
IRνnujol nax（cm-1）：3270，1730，1660，1650
参考例 ９
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩5.0g、炭酸水素ナトリウム7.6gおよびシク
ロヘキシルカルボン酸クロリド4.8gより、Ｎ―
シクロヘキシルカルボニル―（２―フリルカル
ボニル）メチルアミン6.5gを得る。収率91.5％
m.p.110℃〜111℃
IRνnujol nax（cm-1）：3250，3080，1690，1640
(2) Ｎ―シクロヘキシルカルボニル―（２―フリ
ルカルボニル）メチルアミン6.5g、61％水素化
ナトリウム1.3gおよびモノブロモ酢酸エチル
5.1gより、３―シクロヘキシルカルボニルアミ
ノ―３―（２―フリルカルボニル）プロピオン
酸エチル5.0ｇを得る。収率56.2％
m.p.58℃〜61℃
IRνnujol nax（cm-1）：3330，3280，3120，1725，
1680，1640
参考例 10
(1) （２―フリルカルボニル）メチルアミン・塩
酸塩5.0g，炭酸水素ナトリウム6.6gおよびｎ・
カプロイルクロリド4.5gより、Ｎ―ｎ・カプロ
イル―（２―フリルカルボニル）メチルアミン
5.0gを得る。収率77.0％
m.p.64℃〜65℃
IRνnujol nax（cm-1）：3320，3100，1690，1675，
1630
(2) Ｎ―ｎ・カプロイル―（２―フリルカルボニ
ル）メチルアミン5g，61％水素化ナトリウム
1.2gおよびモノブロモ酢酸エチル4.4gより、３
―ｎ・カプロイルアミノ―３―（２―フリルカ
ルボニル）プロピオン酸エチル5.0gを得る。収
率70.4％
m.p.50℃〜51℃
IRνnujol nax（cm-1）：3280，3120，1740，1725，
1675，1640
参考例 11
(1) （３―フリルカルボニル）メチルアミン・塩
酸塩6.0g、炭酸水素ナトリウム7.8gおよび４―
フルオロベンゾイルクロリド6.4gより，Ｎ―４
―フルオロベンゾイル―（３―フリルカルボニ
ル）メチルアミン8.5gを得る。収率92.4％
m.p.142℃〜143℃
IRνnujol nax（cm-1）：3370，3110，1670，1640，
1610
(2) Ｎ―４―フルオロベンゾイル―（３―フリル
カルボニル）メチルアミン8.5g，61％水素化ナ
トリウム1.6gおよびモノブロモ酢酸エチル6.3g
より、３―（４―フルオロベンゾイルアミノ）
―３―（３―フリルカルボニル）プロピオン酸
エチル8.0gを得る。収率69.6％
m.p.107℃〜109℃（分解）
IRνKBr nax（cm-1）：3290，3120，1725，1670，1635
参考例 12
(1) （３―フリルカルボニル）メチルアミン・塩
酸塩6.0g、炭酸水素ナトリウム7.8gおよびベン
ゾイルクロリド5.7gより、Ｎ―ベンゾイル―
（３―フリルカルボニル）メチルアミン7.8gを
得る収率91.8％
m.p.102℃〜103℃
IRνnujol nax（cm-1）：3400，3100，1680，1645，
1610
(2) Ｎ―ベンゾイル―（３―フリルカルボニル）
メチルアミン7.8g，61％水素化ナトリウム1.6g
およびモノブロモ酢酸エチル6.3gより、３―ベ
ンゾイルアミノ―３―（３―フリルカルボニ
ル）プロピオン酸エチル9.2gを得る。取率86.0
％
m.p.108℃〜110℃（分解）
IRνnujol nax（cm-1）：3290，1725，1670，1635
参考例 13
(1) （３―フリルカルボニル）メチルアミン・塩
酸塩5.0g、炭酸水素ナトリウム65gおよび３，
４―ジクロロベンゾイルクロリド6.8gより、Ｎ
―３，４―ジクロロベンゾイル―（３―フリル
カルボニル）メチルアミン7.6gを得る。収率
82.0％
m.p.133℃〜134℃
IRνnujol nax（cm-1）：3460，3360，3130，1680，
1650，1580
(2) Ｎ―３，４―ジクロロベンゾイル―（３―フ
リルカルボニル）メチルアミン7.6g，61％水素
化ナトリウム1.2gおよびモノブロモ酢酸エチル
4.7gより、３―（３，４―ジクロロベンゾイル
アミノ）―３―（３―フリルカルボニル）プロ
ピオン酸エチル9.0gを得る。収率91.9％
m.p.127℃〜129℃（分解）
IRνnujol nax（cm-1）：3330，3180，1715，1690，
1640，1590[Table] Example 26 2-[2-(4-chlorophenyl)-5-(2
-furyl)-4-oxazolyl] 1.0 g of acetic acid, 1.0 g of 2-chloro-1-methylpyridinium iodide, and 0.24 g of isopropanol in tetrahydrofuran.
Dissolve to 30 ml, add 0.8 g of triethylamine dropwise, and stir at room temperature for 10 hours. After adding water to the reaction mixture, tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extracted layer is washed with a 20% aqueous citric acid solution, aqueous sodium bicarbonate, then water, and dried. By distilling off the solvent under reduced pressure and recrystallizing the residue from ethanol, 2-[2-(4-chlorophenyl)-5-
Obtain 0.5 g of (2-furyl)-4-oxazolyl isopropyl acetate. Yield 43.6% mp96℃～97℃ IRν nujol nax (cm -1 ): 3110, 1725 Example 27 2-[2-(4-chlorophenyl)-5-(2
-furyl)-oxazolyl]acetic acid 2.0g, iodide 2
2-[2-(4-chlorophenyl)-5-(2- 2.4 g of lauryl (furyl)-4-oxazolyl acetate was obtained. Yield 77.4% mp69.5℃～71℃ IRν nujol nax (cm -1 ): 3050, 1735 Example 28 2-[2-(4-chlorophenyl)-5-(2
After adding 2.0 g of thionyl chloride to a solution of 2.0 g of chloroform (20 ml of chloroform) at room temperature, the mixture is stirred and refluxed for 3 hours. After cooling, add 0.6g of n-butanol to the reaction solution.
Stir at the same temperature for 6 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extracted layer is washed with an aqueous sodium bicarbonate solution, then with water, and dried. By distilling off the solvent under reduced pressure and recrystallizing the residue from ethanol, 2-[2
-(4-chlorophenyl)-5-(2-furyl)
-4-oxazolyl] 1.5 g of n-butyl acetate was obtained. Yield 62.3% mp96℃～97℃ IRν nujol nax (cm -1 ): 3050, 1730 Example 29 2-[2-(4-chlorophenyl)-5-(2
-furyl)-4-oxazolyl] To a solution of 1.5 g of acetic acid and 1.0 g of n-heptyl bromide in 25 ml of dimethylformamide was added dropwise 0.92 g of triethylamine at room temperature, followed by stirring at 30°C to 40°C for 4 hours.
Pour the reaction into water and extract with diethyl ether:ethyl acetate (1:1). The extracted layer was treated in the same manner as in Example 26 to obtain 0.85 g of n-heptyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate. yield
42.7% mp69℃～70℃ IRν nujol nax (cm -1 ): 3050, 1735 Reference example 1 (1) (2-furylcarbonyl)methylamine hydrochloride 10g, sodium hydrogen carbonate 12.5g, ethyl acetate
Stir 4 into a mixture of 200ml and 100ml water.
-Drop 12.0g of chlorobenzoyl chloride at below 10℃. After further stirring at room temperature for 3 hours,
The ethyl acetate layer is separated, washed with water, and then dried. By distilling off the solvent under reduced pressure, N-4-
Chlorobenzoyl-(2-furylcarbonyl)
Obtain 16.0 g of methylamine. Yield 98.2% mp138℃～139℃ IRν nujol nax (cm -1 ): 3400, 1680, 1660, 1595 (2) Add 40g of N-4-chlorobenzoyl-(2-furylcarbonyl)methylamine to 160ml of dimethylformamide solution Add 7.2 g of 61% sodium hydride with stirring at -50°C to -40°C and stir for an additional 5 minutes. Then, 27.7 g of monobromoethyl acetate was added to the reaction mixture at the same temperature, and the mixture was stirred for 1 hour. The reaction temperature was gradually raised to around 0°C, and the mixture was stirred for an additional hour. After the reaction is complete, the mixture is neutralized with acetic acid, water is added, and extracted with ethyl acetate. The extracted layer is washed with sodium hydrogen carbonate and then with water, and after drying, the solvent is distilled off under reduced pressure. Convert the residue into isopropyl ether
By crystallizing from a mixture of n-hexane,
3-(4-chlorobenzoylamine)-3-
(2-furylcarbonyl)ethyl propionate
Obtain 37.0g. Yield 70% mp100℃～102℃ IRν nujol nax (cm -1 ): 3300, 3100, 1738, 1680,
1630, 1595 Reference Example 2 (1) Dissolve 6.0 g of tertiary butoxypotassium in 60 ml of tetrahydrofuran, and add 4.4 g of methyl α-isocyanoacetate dropwise at -50°C while stirring. After stirring for 1 hour at the same temperature, add 3-
Add 5.8 g of furoyl chloride dropwise at the same temperature while stirring. After further stirring for 2 hours, acetic acid is added to the reaction solution to adjust the pH to 3 to 4, and the mixture is concentrated under reduced pressure to remove the solvent. The residue was extracted with ethyl acetate, the extracted layer was washed with water and a sodium bicarbonate solution, and after drying, the solvent was distilled off under reduced pressure.The residue was washed with isopropyl ether to obtain 5-(3-furyl). 6.5 g of methyl oxazole-4-carboxylate is obtained. yield
75.4% mp87℃～88℃ IRν nujol nax (cm -1 ): 3120, 1695 (2) 3 g of methyl 5-(3-furyl)oxazole-4-carboxylate and 2.6 g of 85% potassium hydroxide
Dissolve in 100 ml of methanol and stir overnight at room temperature. Methanol was distilled off from the reaction solution under reduced pressure, diluted hydrochloric acid was added to the residue to make the liquid acidic, and the precipitated crystals were collected by filtration, washed with cold water and dried to obtain 5-(3-furyl)oxazole. Obtain 2.6 g of -4-carboxylic acid. Yield 93.7% mp189℃～191℃ IRν nujol nax (cm -1 ): 3110, 1700, 1600 (3) A mixture of 3.0g of 5-(3-furyl)oxazole-4-carboxylic acid and 50ml of 2N hydrochloric acid was heated at 40℃
Stir at ~50°C for 6.5 hours. The reaction product was concentrated under reduced pressure, and acetone was added to the residue to crystallize it, which was collected by filtration to obtain 2.2 g of (3-furylbonyl)methylamine hydrochloride. Yield 80% mp196℃～198℃ IRν nujol nax (cm -1 ): 3110, 1680, 1560 (4) (3-furylcarbonyl)methylamine hydrochloride 5g, sodium hydrogen carbonate 6.0g, 4-chlorobenzoyl chloride N-4-chlorobenzoyl-
8.2 g of (3-furylcarbonyl)methylamine are obtained. Yield 100% mp152℃～154℃ IRν nujol nax (cm -1 ): 3350, 3110, 1675, 1635,
1595 (5) Treat in the same manner as in Reference Example 1-(2) using 8.3 g of N-4-chlorobenzoyl-(3-furylcarbonyl)methylamine, 1.5 g of 61% sodium hydride, and 5.8 g of monobromoethyl acetate. 3-(4-chlorobenzoylamino)-3
- Obtain 8.5 g of ethyl (3-furylcarbonyl)propionate. Yield 77.3% mp93℃~95℃ (decomposition) IRν nujol nax (cm -1 ): 3340, 3100, 1705, 1670,
1640 The following compound was produced by the same treatment as in Reference Example 1-(1) and 1-(2). Reference Example 3 (1) From 3.4 g of (2-furylcarbonyl)methylamine hydrochloride, 4.4 g of sodium bicarbonate, and 3.3 g of benzoyl chloride, N-benzoyl-
4.0 g of (2-furylcarbonyl)methylamine is obtained. Yield 83.3% mp132℃～133℃ IRν nujol nax (cm -1 ): 3400, 3100, 1675, 1600 (2) N-benzoyl-(2-furylcarbonyl)
From 4 g of methylamine, 0.8 g of 61% sodium hydride and 3.2 g of ethyl monobromoacetate, 3-benzoylamino-3-(2-furylcarbonyl)
Obtain 4.0 g of ethyl propionate. Yield 72.7% mp75℃～76℃ IRν nujol nax (cm -1 ): 3300, 1715, 1680, 1640 Reference example 4 (1) (2-furylcarbonyl)methylamine hydrochloride 23.4g, sodium hydrogen carbonate 29.3g and 4
- From 23.0g of fluorobenzoyl chloride, N
24.0 g of -4-fluorobenzoyl-(2-furylcarbonyl)methylamine is obtained. Yield 66.8
% mp153℃～155℃ IRν nujol nax (cm -1 ): 3410, 3100, 1680, 1655 (2) N-4-fluorobenzoyl-(2-furylcarbonyl)methylamine 24.0g, 61% sodium hydride 4.7g and monobromoethyl acetate
From 18.4 g, 21.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-furylcarbonyl)propionate was obtained. Yield 64.8% mp95.5℃～97℃ IRν nujol nax (cm -1 ): 3300, 1725, 1690, 1640,
1600 Reference Example 5 (1) (2-furylcarbonyl)methylamine hydrochloride 8.0g, sodium hydrogen carbonate 10.5g and 4
-From 9.2g of methylbenzoyl chloride, N-4
-Methylbenzoyl (2-furylcarbonyl)
Obtain 10.0 g of methylamine. Yield 83.3% mp139℃～141℃ IRν nujol nax (cm -1 ): 3300, 3140, 1690, 1640 (2) N-4-methylbenzoyl-(2-furylcarbonyl)methylamine 12.0g, 61% hydrogenation 2.3g sodium and 9.1g ethyl monobromoacetate
From, 3-(4-methylbenzoylamino)-
13.9 g of ethyl 3-(2-furylcarbonyl)propionate is obtained. Yield 85.5% mp83.5℃～84.5℃ IRν nujol nax (cm -1 ): 3300, 3250, 1710, 1680,
1640, 1610 Reference example 6 (1) (2-furylcarbonyl)methylamine hydrochloride 8.0g, sodium hydrogen carbonate 10.5g and 4
- From 10.1g of methoxybenzoyl chloride, N
11.0 g of -4-methoxybenzoyl-(2-furylcarbonyl)methylamine is obtained. Yield 85.3
% mp114℃～115℃ IRν nujol nax (cm -1 ): 3310, 3150, 1690, 1635 (2) N-4-methoxybenzoyl-(2-furylcarbonyl)methylamine 11.0g, 61% sodium hydride 2.0 g and ethyl monobromoacetate
From 7.8g, 10.7g of ethyl 3-(4-methoxybenzoylamino)-3-(2-fururicabonyl)propionate was obtained. Yield 72.8% mp104℃～106℃ IRν nujol nax (cm -1 ): 3300, 1715, 1680, 1635,
1610 Reference Example 7 (1) 3.2 g of (2-furylcarbonyl)methylamine hydrochloride and 10 ml of acetic anhydride in 50 ml of ethyl acetate
Drop an aqueous solution of sodium hydrogen carbonate into the solution at room temperature while stirring until the liquid becomes alkaline. After stirring for an additional hour, the ethyl acetate layer was separated, washed with water, and dried. The solvent is distilled off under reduced pressure and the residue is washed with isopropyl ether to obtain 1.5 g of N-acetyl-(2-furylcarbonyl)methylamine. Yield 45.0% mp114℃～115℃ IRν nujol nax (cm -1 ): 3380, 3090, 1670, 1655 (2) N-acetyl-(2-furylcarbonyl)methylamine 2.6g, 61% sodium hydride 0.74g
and 2.9 g of ethyl monobromoacetate, 3-acetylamino-3-(2-furylcarbonyl)
Obtain 1.6 g of ethyl propionate. Yield 41% mp82℃～84℃ IRν nujol nax (cm -1 ): 3280, 3100, 1680, 1650 Reference example 8 (1) (2-furylcarbonyl)methylamine hydrochloride 16.0g, sodium hydrogen carbonate 20.5g and N-isobutyryl-(2-furylcarbonyl)methylamine from 11.4 g of isobutyl chloride.
Obtain 13.0g. Yield 67.0% mp78℃～80℃ IRν nujol nax (cm -1 ): 3300, 3130, 1680, 1640 (2) N-isobutyryl-(2-furylcarbonyl)methylamine 13.0g, 61% sodium hydride 3.1g and 12.2g of ethyl monobromoacetate,
12.0 g of ethyl 3-isobutyrylamino-3-(2-furylcarbonyl)propionate is obtained.
Yield 64.2% mp65℃～67℃ IRν nujol nax (cm -1 ): 3270, 1730, 1660, 1650 Reference example 9 (1) (2-furylcarbonyl)methylamine hydrochloride 5.0g, sodium hydrogen carbonate 7.6g and 4.8 g of cyclohexylcarboxylic acid chloride, N-
6.5 g of cyclohexylcarbonyl-(2-furylcarbonyl)methylamine are obtained. Yield 91.5% mp110℃~111℃ IRν nujol nax (cm -1 ): 3250, 3080, 1690, 1640 (2) N-cyclohexylcarbonyl-(2-furylcarbonyl)methylamine 6.5g, 61% sodium hydride 1.3 g and ethyl monobromoacetate
From 5.1 g, 5.0 g of ethyl 3-cyclohexylcarbonylamino-3-(2-furylcarbonyl)propionate was obtained. Yield 56.2% mp58℃～61℃ IRν nujol nax (cm -1 ): 3330, 3280, 3120, 1725,
1680, 1640 Reference example 10 (1) (2-furylcarbonyl)methylamine hydrochloride 5.0g, sodium hydrogen carbonate 6.6g and n.
From 4.5g of caproyl chloride, N-n.caproyl-(2-furylcarbonyl)methylamine
Get 5.0g. Yield 77.0% mp64℃～65℃ IRν nujol nax (cm -1 ): 3320, 3100, 1690, 1675,
1630 (2) N-n.caproyl-(2-furylcarbonyl)methylamine 5g, 61% sodium hydride
From 1.2g and 4.4g of monobromoethyl acetate, 3
-5.0 g of ethyl n.caproylamino-3-(2-furylcarbonyl)propionate is obtained. Yield 70.4% mp50℃～51℃ IRν nujol nax (cm -1 ): 3280, 3120, 1740, 1725,
1675, 1640 Reference example 11 (1) (3-furylcarbonyl)methylamine hydrochloride 6.0g, sodium hydrogen carbonate 7.8g and 4-
From 6.4g of fluorobenzoyl chloride, N-4
8.5 g of -fluorobenzoyl-(3-furylcarbonyl)methylamine is obtained. Yield 92.4% mp142℃～143℃ IRν nujol nax (cm -1 ): 3370, 3110, 1670, 1640,
1610 (2) 8.5 g N-4-fluorobenzoyl-(3-furylcarbonyl)methylamine, 1.6 g 61% sodium hydride and 6.3 g ethyl monobromoacetate
From, 3-(4-fluorobenzoylamino)
8.0 g of ethyl -3-(3-furylcarbonyl)propionate was obtained. Yield 69.6% mp107℃～109℃(decomposition) IRν KBr nax (cm -1 ): 3290, 3120, 1725, 1670, 1635 Reference example 12 (1) (3-furylcarbonyl)methylamine hydrochloride 6.0g, From 7.8g of sodium hydrogen carbonate and 5.7g of benzoyl chloride, N-benzoyl-
Yield 91.8% to obtain 7.8 g of (3-furylcarbonyl)methylamine mp102℃~103℃ IRν nujol nax (cm -1 ): 3400, 3100, 1680, 1645,
1610 (2) N-benzoyl-(3-furylcarbonyl)
Methylamine 7.8g, 61% sodium hydride 1.6g
From 6.3 g of ethyl monobromoacetate, 9.2 g of ethyl 3-benzoylamino-3-(3-furylcarbonyl)propionate was obtained. Take rate 86.0
% mp108℃～110℃(decomposition) IRν nujol nax (cm -1 ): 3290, 1725, 1670, 1635 Reference example 13 (1) (3-furylcarbonyl)methylamine hydrochloride 5.0g, sodium hydrogen carbonate 65g and 3,
From 6.8g of 4-dichlorobenzoyl chloride, N
7.6 g of -3,4-dichlorobenzoyl-(3-furylcarbonyl)methylamine is obtained. yield
82.0% mp133℃～134℃ IRν nujol nax (cm -1 ): 3460, 3360, 3130, 1680,
1650, 1580 (2) 7.6 g of N-3,4-dichlorobenzoyl-(3-furylcarbonyl)methylamine, 1.2 g of 61% sodium hydride and ethyl monobromoacetate
From 4.7g, 9.0g of ethyl 3-(3,4-dichlorobenzoylamino)-3-(3-furylcarbonyl)propionate is obtained. Yield 91.9% mp127℃~129℃ (decomposition) IRν nujol nax (cm -1 ): 3330, 3180, 1715, 1690,
1640, 1590
Claims (1)
もしくはフエニル基であるか、またはアルキル
基、アルコキシ基及びハロゲン原子から選ばれる
１〜２個の置換基を有するフエニル基を表わし、
R2は水素原子又はアルキル基を表わす） で示されるフリルオキサゾリル酢酸誘導体。 ２ 一般式〔〕において、R2が水素原子であ
る特許請求の範囲第１項記載の化合物。 ３ 一般式〔〕において、R2がアルキル基で
ある特許請求の範囲第１項記載の化合物。 ４ 化合物が薬理的に許容しうる塩である特許請
求の範囲第２項記載の化合物。 ５ 一般式〔〕において、R1が４―ハロゲノ
フエニル基であり、かつハロゲン原子が塩素原子
またはフツ素原子である特許請求の範囲第１項、
第２項、第３項または第４項記載の化合物。[Claims] 1. General formula (However, R 1 is an alkyl group, a cycloalkyl group, or a phenyl group, or represents a phenyl group having 1 to 2 substituents selected from an alkyl group, an alkoxy group, and a halogen atom,
(R 2 represents a hydrogen atom or an alkyl group) A furyloxazolyl acetic acid derivative represented by: 2. The compound according to claim 1, wherein in the general formula [], R 2 is a hydrogen atom. 3. The compound according to claim 1, wherein in the general formula [], R 2 is an alkyl group. 4. The compound according to claim 2, wherein the compound is a pharmacologically acceptable salt. 5. Claim 1, wherein in the general formula [], R 1 is a 4-halogenophenyl group, and the halogen atom is a chlorine atom or a fluorine atom,
A compound according to item 2, 3 or 4.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57030921A JPS58148882A (en) | 1982-02-26 | 1982-02-26 | Furyloxazolylacetic acid derivative and its preparation |
| US06/465,544 US4642313A (en) | 1982-02-26 | 1983-02-10 | Furyloxazolylacetic acid derivatives and processes for preparing same |
| CA000422117A CA1194483A (en) | 1982-02-26 | 1983-02-22 | Furyloxazolylacetic acid derivatives and processes for preparing same |
| DK82583A DK82583A (en) | 1982-02-26 | 1983-02-23 | FURYLOXAZOLYL ACETIC ACID DERIVATIVES AND PROCEDURES FOR PRODUCING THEREOF |
| BG8359855A BG39977A3 (en) | 1982-02-26 | 1983-02-24 | Method for preparing derivatives of furyloxazolylacetic acid |
| DE8383101872T DE3363575D1 (en) | 1982-02-26 | 1983-02-25 | Furyloxazolylacetic acid derivatives, process for preparing same and pharmaceutical compositions containing same |
| AT83101872T ATE19879T1 (en) | 1982-02-26 | 1983-02-25 | FURILOXAZOLYLACETIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| EP83101872A EP0087782B1 (en) | 1982-02-26 | 1983-02-25 | Furyloxazolylacetic acid derivatives, process for preparing same and pharmaceutical compositions containing same |
| HU83658A HU193648B (en) | 1982-02-26 | 1983-02-25 | Process for production of derivatives of furil-oxasolile acetic acid and medical preparatives containing those |
| KR1019830000770A KR900001423B1 (en) | 1982-02-26 | 1983-02-25 | Process for preparing furyloxazolyl acetic acid derivatives |
| ES520136A ES8403891A1 (en) | 1982-02-26 | 1983-02-25 | Furyloxazolylacetic acid derivatives, process for preparing same and pharmaceutical compositions containing same. |
| SU833555401A SU1169536A3 (en) | 1982-02-26 | 1983-02-25 | Method of obtaining derivatives of furyloxazolylacetic acid of their pharmaceutically acceptable salts |
| SG106/88A SG10688G (en) | 1982-02-26 | 1988-02-06 | Furyloxazolylacetic acid derivatives, process for preparing same and pharmaceutical compositions containing same |
| HK871/88A HK87188A (en) | 1982-02-26 | 1988-10-27 | Furyloxazolylacetic acid derivatives,process for preparing same and pharmaceutical compositions containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57030921A JPS58148882A (en) | 1982-02-26 | 1982-02-26 | Furyloxazolylacetic acid derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58148882A JPS58148882A (en) | 1983-09-05 |
| JPS635027B2 true JPS635027B2 (en) | 1988-02-01 |
Family
ID=12317149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57030921A Granted JPS58148882A (en) | 1982-02-26 | 1982-02-26 | Furyloxazolylacetic acid derivative and its preparation |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4642313A (en) |
| EP (1) | EP0087782B1 (en) |
| JP (1) | JPS58148882A (en) |
| KR (1) | KR900001423B1 (en) |
| AT (1) | ATE19879T1 (en) |
| BG (1) | BG39977A3 (en) |
| CA (1) | CA1194483A (en) |
| DE (1) | DE3363575D1 (en) |
| DK (1) | DK82583A (en) |
| ES (1) | ES8403891A1 (en) |
| HK (1) | HK87188A (en) |
| HU (1) | HU193648B (en) |
| SG (1) | SG10688G (en) |
| SU (1) | SU1169536A3 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59152382A (en) * | 1983-02-18 | 1984-08-31 | Tanabe Seiyaku Co Ltd | Furyloxazolylacetic acid derivative and its preparation |
| CA2160440C (en) * | 1994-10-13 | 1998-08-25 | Louis G. Lange, Iii | Method of manufacturing non-absorbable synthetic sulfated polysaccharides |
| US7071174B1 (en) | 1994-10-13 | 2006-07-04 | Cv Therapeutics, Inc. | Method and composition for inhibiting cholesterol esterase |
| CZ20032829A3 (en) * | 2001-04-16 | 2005-03-16 | Tanabe Seiyaku Co., Ltd. | Heterocyclic compounds |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE32084B1 (en) * | 1967-06-07 | 1973-04-04 | Wyeth John & Brother Ltd | Thiazole derivatives |
| FI53314C (en) * | 1967-06-14 | 1978-04-10 | Wyeth John & Brother Ltd | PROCEDURE FOR THE FRAMEWORK OF PHARMACEUTICALS ANVAENDBAR 2- (PHENYLELLER P-CHLORPHENYL) OXAZOL-4-YL |
| GB1245087A (en) * | 1967-10-26 | 1971-09-02 | Wyeth John & Brother Ltd | Heterocyclic compounds |
| US3578671A (en) * | 1967-11-06 | 1971-05-11 | Wyeth John & Brother Ltd | Oxazoles |
| FR2068418A1 (en) * | 1969-10-27 | 1971-08-27 | Innothera Lab Sa | 2-substd-5-amino isoxazole derivs |
| AR208400A1 (en) * | 1974-03-13 | 1976-12-27 | Yoshitomi Pharmaceutical | A METHOD TO PRODUCE NEW 2-SUBSTITUTED 5-ALCOXI-4-OXAZOLALKANOIC ACIDS AND THEIR ESTERS |
| JPS51110039A (en) * | 1975-02-28 | 1976-09-29 | Yoshitomi Pharmaceutical | KETSUCHUSHI SHITSUTAISHAKAIZENZAI |
| GB1542315A (en) * | 1976-08-13 | 1979-03-14 | Wyeth John & Brother Ltd | Process for preparing oxazoles |
| JPS5677268A (en) * | 1979-11-28 | 1981-06-25 | Yoshitomi Pharmaceut Ind Ltd | Oxazoleacetic acid derivative |
| JPS57188587A (en) * | 1981-05-15 | 1982-11-19 | Tanabe Seiyaku Co Ltd | Thienyloxazolylacetic acid derivative and its preparation |
-
1982
- 1982-02-26 JP JP57030921A patent/JPS58148882A/en active Granted
-
1983
- 1983-02-10 US US06/465,544 patent/US4642313A/en not_active Expired - Fee Related
- 1983-02-22 CA CA000422117A patent/CA1194483A/en not_active Expired
- 1983-02-23 DK DK82583A patent/DK82583A/en not_active Application Discontinuation
- 1983-02-24 BG BG8359855A patent/BG39977A3/en unknown
- 1983-02-25 DE DE8383101872T patent/DE3363575D1/en not_active Expired
- 1983-02-25 ES ES520136A patent/ES8403891A1/en not_active Expired
- 1983-02-25 KR KR1019830000770A patent/KR900001423B1/en not_active IP Right Cessation
- 1983-02-25 EP EP83101872A patent/EP0087782B1/en not_active Expired
- 1983-02-25 HU HU83658A patent/HU193648B/en not_active IP Right Cessation
- 1983-02-25 AT AT83101872T patent/ATE19879T1/en active
- 1983-02-25 SU SU833555401A patent/SU1169536A3/en active
-
1988
- 1988-02-06 SG SG106/88A patent/SG10688G/en unknown
- 1988-10-27 HK HK871/88A patent/HK87188A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HK87188A (en) | 1988-11-04 |
| EP0087782A1 (en) | 1983-09-07 |
| EP0087782B1 (en) | 1986-05-21 |
| JPS58148882A (en) | 1983-09-05 |
| KR840003632A (en) | 1984-09-15 |
| DE3363575D1 (en) | 1986-06-26 |
| KR900001423B1 (en) | 1990-03-09 |
| DK82583A (en) | 1983-08-27 |
| ATE19879T1 (en) | 1986-06-15 |
| SU1169536A3 (en) | 1985-07-23 |
| ES520136A0 (en) | 1984-04-01 |
| US4642313A (en) | 1987-02-10 |
| ES8403891A1 (en) | 1984-04-01 |
| BG39977A3 (en) | 1986-09-15 |
| SG10688G (en) | 1988-07-01 |
| CA1194483A (en) | 1985-10-01 |
| DK82583D0 (en) | 1983-02-23 |
| HU193648B (en) | 1987-11-30 |
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